Impact of natural genetic variation on enhancer selection and function

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here, we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics, and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence supporting the concept that lineage-determining transcription factors (LDTFs) define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for LDTFs and informative histone modifications can be used for prioritization of disease-associated regulatory variants.